National Multicenter, Controlled, Single-blind Study With Two Parallel Groups Evaluating the Safety and Efficacy of Sequential Treatment With Mitoxantrone and Interferon Versus Interferon Alone in Patients With Strong Risk of Progression in the Initial Phase of Multiple Sclerosis

Rennes University Hospital35 enrolled

Overview

The relative effectiveness of current treatments and their different mechanisms of action yield to consider more and more that the multiple sclerosis (MS) therapeutic approach must use multiple molecules, both combined and sequential. In this sense, one can assume that the combination of two molecules with different but complementary mechanisms of action, can delay progression of the disease. Mitoxantrone has a powerful action, immediate and total, whereas interferon a selective action, immunomodulatory and delayed.

This study is based on the hypothesis that there is a synergistic effect of both increasing the dose of interferon and also the use of mitoxantrone, allowing to further reduce the conversion rate MS. Because mitoxantrone decreases the rate of relapses 2 times more than interferon beta, a (at least) 2 times higher benefit on the disease activity is expected with interferon mitoxantrone combination than with interferon alone.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Enrollment

Conditions

Multiple Sclerosis

Interventions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 50 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Patients should have a MS according to the McDonald criteria: * One relapse with time dissemination shown by an MRI performed less than 2 months before inclusion, with at least one of these criteria: * multifocal presentation * relapse determining a severe disability (EDSS greater than 3.5) * at least 2 lesions taking contrast on MRI * at least 9 T2 lesions with contrast enhancement. * Patients must be 18 to 50 years. * The duration of disease progression should be less than one year. * Women of childbearing age must have an effective contraception. * Patients have to be able to give their own informed consent before inclusion in the study. Exclusion Criteria: * presence of another disease that could explain the symptoms / signs of the patient. * Any other condition / disability that may interfere with the clinical state. * Prior treatment with immunosuppressive (mitoxantrone, azathioprine, cyclophosphamide) or immunomodulator. * Treatment with corticosteroids in the previous 2 weeks, regardless of the dose. * Corticosteroids for over a month. * Pregnancy and lactation. * Patient whose antecedents may contra-indicate the use of immunosuppressive therapy. * Hypersensitivity to mitoxantrone or one of the excipients. * Clinical cardiac disease with reduced ejection fraction of the left ventricle. * Patient suffering from myelodysplasia. * Abnormalities of Complete Blood Count. * History of hematologic malignancy. * Hepatic impairment. * Vaccination against yellow fever. * Vaccination with an attenuated vaccine assets. * Treatment with phenytoin or fosphenytoin. * Hypersensitivity to interferon beta-1a natural or recombinant or any of the excipients. * Current severe depression and / or suicidal thoughts. * Uncontrolled epilepsy. * History of addiction. * A history of hypersensitivity to gadolinium, history of severe renal impairment * Inability to undergo MRI (claustrophobia, tics, involuntary movements, tremor, etc.). * Participation in another trial in the preceding 6 months or during the study. * Minors, protected adults and persons deprived of their liberty.

Outcomes

Primary Outcomes

Treatment efficacy

Efficacy is judged based on * the absence of relapse within the 2 first years; AND * a disease progression as determined by an increase in the Expanded Disability Status Scale (EDSS) not greater than 1 during the 4 years treatment.

Time frame: Four years after inclusion

Secondary Outcomes

Time to first relapse

Time frame: From date of randomization until the date of first documented progression, assessed up to 4 years

Frequency of relapses in 2 years

Time frame: Within two years following randomization

Frequency of relapses in 4 years

Time frame: Within four years following randomization

Changes in the level of disability in 2 years

EDSS score

Time frame: Two years following randomization

Changes in the level of disability in 4 years

EDSS score

Time frame: Four years following randomization

Patients in progression

Rate of patients who progressed to a clinically definite MS (according to the criteria of Mc Donald) in the subgroup of patients who had only one clinical event.

Time frame: Four years following randomization

Disease activity on MRI at 6 months

To compare in the two arms, the rate of patients without radiological (MRI) sign of disease activity

Time frame: 6 months following randomization

Patients without disease activity on MRI at 12 months

To compare in the two arms, the rate of patients without radiological (MRI) sign of disease activity

Time frame: 12 months following randomization

Patients without disease activity on MRI at 24 months

To compare in the two arms, the rate of patients without radiological (MRI) sign of disease activity

Time frame: 24 months following randomization

Patients without disease activity on MRI at 48 months

To compare in the two arms, the rate of patients without radiological (MRI) sign of disease activity

Time frame: 48 months following randomization

Number of visible lesions on MRI at 6 months

To compare in the two arms, the number of lesions taking contrast

Time frame: 6 months following randomization

Number of visible lesions on MRI at 12 months

To compare in the two arms, the number of lesions taking contrast

Time frame: 12 months following randomization

Number of visible lesions on MRI at 24 months

To compare in the two arms, the number of lesions taking contrast

Time frame: 24 months following randomization

Number of visible lesions on MRI at 48 months

To compare in the two arms, the number of lesions taking contrast

Time frame: 48 months following randomization

Lesion load on evaluated T2 weighted MRI at 12 months

Time frame: 12 months following randomization

Lesion load on evaluated T2 weighted MRI at 24 months

Time frame: 24 months following randomization

Lesion load on evaluated T2 weighted MRI at 48 months

Time frame: 48 months following randomization

Brain atrophy

To assess the presence and progression of brain atrophy, changes in the total brain volume after 24 and 48 months will be automatically measured from MR images with dedicated software and expressed as percent change, from a standardized estimation of cerebral volume.

Time frame: 24 and 48 months following randomization

National Multicenter, Controlled, Single-blind Study With Two Parallel Groups Evaluating the Safety and Efficacy of Sequential Treatment With Mitoxantrone and Interferon Versus Interferon Alone in Patients With Strong Risk of Progression in the Initial Phase of Multiple Sclerosis

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes